# Macrophage mitochodrial reprogramming and innate immune memory

> **NIH NIH R01** · VANDERBILT UNIVERSITY MEDICAL CENTER · 2022 · $424,961

## Abstract

Project Summary
Hospital-acquired infections are a major threat to public health, impacting 2 million patients and causing at
least 90,000 deaths annually. Sepsis is a common complication in patients with hospital-acquired infections
and the leading cause of death in non-cardiac intensive care units (ICU). Attempts at treating hospital-acquired
infections and sepsis have proven exceedingly difficult and patients that survive sepsis suffer long-term
physical and cognitive disabilities and a high 1-year mortality rate. Therefore, new strategies are needed to
decrease the burden of hospital-acquired infections and sepsis. Immunotherapy aimed at inducing
innate immune memory provides a way of achieving that goal. Recent studies show that innate immune
cells can retain memory of prior pathogen exposure and are primed to elicit a robust, broad-spectrum
antimicrobial response to subsequent infection. Treatment with TLR4 ligands, such as monophosphoryl lipid A
(MPLA), confers innate immune memory and resistance to a broad array of clinically important pathogens that
persists for more than 2 weeks. We propose that the appropriate application of TLR4 ligand-based
immunotherapy to induce innate immune memory has significant potential to reduce the burden of
hospital-acquired infections and sepsis. Macrophages are the foundation for development of innate
immune memory. Recent evidence indicates that remodeling of macrophage metabolism is central to the
induction of innate immune memory. Priming with TLR4 ligands induces a macrophage metabolic phenotype
characterized by increased glycolysis, oxidative metabolism and mitochondrial biogenesis with increased citric
acid cycle flux and associated increases in immunoresponsive gene 1 (Irg1) expression and itaconate
production. We hypothesize that macrophage metabolic remodeling and the increased production of
Irg1 and itaconate are essential to generating innate immune memory. To define the underlying biology,
we will: (1). Determine how Irg1 and itaconate drive TLR4 agonist-induced innate immune memory in
macrophages; (2). Define the importance of Irg1, itaconate and Nrf2 as regulators of the host response to
infection with common hospital-acquired pathogens after TLR4 agonist treatment in vivo.; (3). Define the
intracellular signaling pathways driving mitochondrial biogenesis, Irg1 expression and itaconate production in
TLR4 agonist-primed macrophages; (4). Determine the ability of diverse microbial ligands to induce
macrophage mitochondrial biogenesis, reprogram mitochondrial metabolism and function and induce innate
immune memory. We will test the hypothesis that, like TLR4 agonists, microbial ligands such as peptidoglycan,
CpG ODN and β-glucan, have the ability to reprogram macrophage metabolism and induce a memory
phenotype characterized by mitochondrial biogenesis, increased citric acid cycle flux, increased Irg1
expression and itaconate production with associated enhancement of antimicrobial functions.

## Key facts

- **NIH application ID:** 10333362
- **Project number:** 5R01AI151210-03
- **Recipient organization:** VANDERBILT UNIVERSITY MEDICAL CENTER
- **Principal Investigator:** EDWARD R SHERWOOD
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $424,961
- **Award type:** 5
- **Project period:** 2020-02-13 → 2025-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10333362

## Citation

> US National Institutes of Health, RePORTER application 10333362, Macrophage mitochodrial reprogramming and innate immune memory (5R01AI151210-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10333362. Licensed CC0.

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